8,10,12 as nanoreactors for non-enzymatic introduction of: Ortho, meta or para -hydroxyl groups to aromatic molecules

Article abstract of DOI:10.1039/c7dt00373k

Traditional electrophilic bromination follows long established "rules": electron-withdrawing substituents cause bromination selective for meta positions, whereas electron-donating substituents favor ortho and para bromination. In contrast, in the [PhSiO_1.5]_8,10,12 silsesquioxanes, the cages act as bulky, electron withdrawing groups equivalent to CF₃; yet bromination under mild conditions, without a catalyst, greatly favors ortho substitution. Surprisingly, ICl iodination without a catalyst favors (>90%) para substitution [p-IC₆H₄SiO_1.5]_8,10,12. Finally, nitration and Friedel-Crafts acylation and sulfonylation are highly meta selective, >80%. In principle, the two halogenation formats coupled with the traditional electrophilic reactions provide selective functionalization at each position on the aromatic ring. Furthermore, halogenation serves as a starting point for the synthesis of two structural isomers of practical utility, i.e. in drug prospecting. The o-bromo and p-iodo compounds are easily modified by catalytic cross-coupling to append diverse functional groups. Thereafter, F^-/H₂O₂ treatment cleaves the Si-C bonds replacing Si with OH. This represents a rare opportunity to introduce hydroxyl groups to aromatic rings, a process not easily accomplished using traditional organic synthesis methods. The as-produced phenol provides additional opportunities for modification. Each cage can be considered a nanoreactor generating 8-12 product molecules. Examples given include syntheses of 4,2′-R,OH-stilbenes and 4,4′-R,OH-stilbenes (R = Me, CN). Unoptimized cleavage of the Br/I derivatives yields 55-85% phenol. Unoptimized cleavage of the stilbene derivatives yields 35-40% (3-5 equivalents of phenol) in the preliminary studies presented here. In contrast, meta R-phenol yields are 80% (7-10 mol per cage).

Full text of DOI:10.1039/c7dt00373k

View Article Online
View Journal
Dalton
Transactions
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Bahrami, X.
Zhang, M. Ehsani, Y. Jahani and R. M. Laine, Dalton Trans., 2017, DOI: 10.1039/C7DT00373K.
This is an Accepted Manuscript, which has been through the
Volume 45 Number
1 7 January 2016 Pages 1–398
Royal Society of Chemistry peer review process and has been
accepted for publication.
Dalton
Transactions
Accepted Manuscripts are published online shortly after
An international journal of inorganic chemistry
www.rsc.org/dalton
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-9226
PAPER
Joseph T. Hupp, Omar K. Farha et al.
Efficient extraction of sulfate from water using
framework
a Zr-metal–organic
rsc.li/dalton

Page 1 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
[PhSiO1.5]8,10,12 as nanoreactors for non-enzymatic introduction of ortho, meta or para-
hydroxyl groups to aromatic molecules.
Mozghan Bahrami,1,2 Xingwen Zhang,1,3 Morteza Ehsani,2 Yousef Jahani,2 Richard M. Laine1*
1Macromolecular Science and Engineering, and Materials Science and Engineering, University
of Michigan, Ann Arbor, MI 48109ꢀ2136, 2Department of Polymer Processing, Iran Polymer and
Petrochemical Institute, 14965/115, Tehran, Iran. 3Department of Chemistry, Harbin Institute of
Technology, Harbin 150001, China.
Abstract
Traditional electrophilic bromination follows long established “rules:” electronꢀwithdrawing
substituents cause bromination selective for meta positions, whereas, electronꢀdonating substituꢀ
ents favor ortho and para bromination. In contrast, in the [PhSiO1.5]8,10,12 silsesquioxanes, the
cages act as bulky, electron withdrawing groups equivalent to CF3; yet bromination under mild
conditions, without catalyst, greatly favors ortho substitution. Surprisingly, ICl iodination with-
out catalyst favors (>90 %) para substitution [pꢀIC6H4SiO1.5]8,10,12. Finally, nitration and Friedelꢀ
Crafts acylation and sulfonylation are highly meta selective, > 80 %.
In principle, the two halogenation formats coupled with the traditional electrophilic reactions
provide selective functionalization at each position on the aromatic ring. Furthermore, halogenaꢀ
tion serves as a starting point for the synthesis of two structural isomers of practical utility, i.e. in
drug prospecting. The o-bromo and p-iodo compounds are easily modified by catalytic crossꢀ
coupling to append diverse functional groups. Thereafter, Fꢀ/H2O2 treatment cleaves the SiꢀC
bonds replacing Si with OH. This represents a rare opportunity to introduce hydroxyl groups to
aromatic rings, a process not easily accomplished using traditional organic synthesis methods.
The asꢀproduced phenol provides additional opportunities for modification. Each cage can be
considered a nanoꢀreactor generating 8ꢀ12 product molecules. Examples given include syntheses
of 4,2’-R,OH-stilbenes and 4,4’-R,OH-stilbenes (R = Me, CN). Unoptimized cleavage of the Br/I
derivatives yields 55ꢀ85% phenol. Unoptimized cleavage of the stilbene derivatives yields 35ꢀ40
% (3ꢀ5 equivalents of phenol) in the preliminary studies presented here. In contrast, meta Rꢀ
phenol yields are 80 % (7ꢀ10 mols per cage).
1

Dalton Transactions
Page 2 of 25
View Article Online
DOI: 10.1039/C7DT00373K
Introduction
Hydroxylated aromatics (e.g. phenols) are categorized as largeꢀscale commodities, organic
intermediates and as important precursors in the pharmaceutical and agrochemical industries.1ꢀ15
However, the introduction of hydroxyl groups to aromatic systems requires a moderately active
oxygen species that does not coincidentally destroy the product via total oxidation. A recent pubꢀ
lication describes the smooth CꢀSi bond cleavage of organosilicon compounds with NBS and mꢀ
CPBA to produce the corresponding pꢀphenols, which complements the work reported here.16
Hydrogen peroxide has several advantages over other common, low cost oxidants, most of
them prepared from hydrogen peroxide itself. The active oxygen content for H2O2 exceeds all
others save O3. Further, from an economic perspective the only byproduct is H2O.17ꢀ19
In commercial practice, Fenton’s reagent (Fe3+/H2O2) is an important tool as it produces exꢀ
tremely reactive hydroxyl radicals often used to treat industrial waste containing toxic organics
like benzene, phenol, dyes and pesticides in wastewater, sludges or contaminated soils to reduce
toxicity, improve biodegradability and decolorize.20ꢀ23 It can also be used for oxyfunctionalizaꢀ
tion of saturated hydrocarbons to the corresponding alcohols, aldehydes, ketones and carboxylic
acids.24,25 Despite its numerous advantages, e.g. inexpensive water phase oxidation, its lack of
selective oxidation and high oxygen reactivity frequently lead to over oxidation, limiting its synꢀ
thetic utility.26ꢀ27
A review of the stateꢀofꢀtheꢀart in selective hydroxylation of aromatic compounds suggests
that oxidative cleavage of the SiꢀC bonds in [RPhSiO1.5]8,10,12 using FlemingꢀTamao reagents
represents a less explored but potentially quite viable approach to a wide variety of functionalꢀ
ized phenols.
2

Page 3 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
The FlemingꢀTamao oxidation of SiꢀC bonds has been used extensively in the generation of
hydroxyl groups at carbon;28ꢀ35 and is particularly invaluable in natural products syntheses. In
general, simple trimethyl and dimethylphenylsilyl groups have been used as “masked” hydroxyl
groups. Synthetic routes that employ FlemingꢀTamao oxidation as a means of generating substiꢀ
tuted phenols are much less well known.34,35 Indeed, general and relatively unaggressive methods
of generating phenolic compounds seem to be an area that deserves more attention.
Our recent efforts to use Fꢀ/H2O2 promoted cleavage of the SiꢀC bonds in [RPhSiO1.5]8,10,12 to
form phenols simply to verify substitution patterns on the cage phenyls provided the initial impeꢀ
tus for the current work. Further motivation comes from the fact that o-bromination is highly
favored in the [PhSiO1.5]8,10,12 cages [selectivity is 85 % in [PhSiO1.5]8, 70 % in [PhSiO1.5]10 and
60 % in [PhSiO1.5]12 ].36,37 This contrasts greatly with iodination with ICl which occurs almost
exclusively in the para position [90ꢀ95 % para for all cages].38,39 Both of these reactions contrast
with traditional nitration and Friedel Crafts acylation and sulfonylation of these cages where subꢀ
stitution at the meta position is highly favored [>80 % for all cages].40ꢀ42
Both oꢀBr and pꢀI compounds are easily functionalized by traditional catalytic cross coupling
to introduce the same moieties.43ꢀ45 We are now able to cleave the SiꢀC bonds in these comꢀ
pounds to introduce hydroxyl groups in the ortho, meta, or para positions as we demonstrate
below. Because each [RPhSiO1.5]8,10,12 cage will contain 8, 10 or 12 moieties with the same funcꢀ
tionality on one cage, Fꢀ/H2O2 cleavage will produce multiple examples of the same product,
hence the term nanoreactor.
Thus, given that the literature indicates that there are very few, efficient methods of introducꢀ
ing hydroxyl groups to aromatic molecules with the most successful being enzymatic,46ꢀ53 and
given the importance that aromatic hydroxyl groups play in drug discovery for example;46,47 we
3

Dalton Transactions
Page 4 of 25
View Article Online
DOI: 10.1039/C7DT00373K
initiated efforts to first understand the mechanism whereby selective ortho bromination occurs in
the [PhSiO1.5]8,10,12 cages, as discussed recently.36,37 The current work represents efforts to show
the generality of the cleavage reaction to form phenols with only limited efforts to optimize conꢀ
versions. These efforts are summarized in Scheme 1.
For perspective purposes, the direct oxidation of benzonitrile to hydroxybenzonitriles was
explored using nitrous oxide as oxidant with zeolite catalysts.52 Fe free catalysts give ≤ 73% seꢀ
lectivity to hydroxybenzonitriles at benzonitrile conversions of 10%. Three isomers are produced
with an o:m:p ratio of 1:6:3.52 Although not reported, one presumes that at higher conversions
the initial products are further oxidized thereby limiting conversion efficiencies.
In another study, chemically modified graphene (CCG) was used to catalyze the direct oxidaꢀ
tion of benzene to phenol using hydrogen peroxide as the oxidant.53 Conversion efficiencies of
18ꢀ20 % provided phenol with 98 % selectivities.53 Again, higher conversions were not reported
presumably for the same reasons.
Scheme 1. [RPhSiO1.5]10 cage compounds provide access to diverse ortho, meta, and para hyꢀ
droxylated aromatic compounds and 2,5ꢀdibromophenol in moderate to high yields. (Purple: Or-
tho, Green: Meta, Red: Para, Blue: difunctional)
4

Page 5 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
Experimental Methods
Materials. The compounds [PhSiO1.5]8,12 and [m-NitroPhSiO1.5]8 were received as a gift from
Mayaterials Inc. [PhSiO1.5]10 was prepared using literature methods.54 Bromine, ICl (1.0 M in
dichloromethane) and other synthetic reagents were purchased from Sigma Aldrich and used as
received. Dichloromethane (CH2Cl2) was purchased from Fisher Scientific and distilled from
CaH2 under N2 prior to use. Dioxane and THF were purchased from Fisher Scientific and disꢀ
tilled from Na/benzophenone under N2 prior to use.
36
55
39
[oꢀBrPhSiO1.5]10,36 [o-BrPhSiO1.5]12, [o-BrPhSiO1.5]8, [p-IPhSiO1.5]12 were synthesized
using literature procedures.
General Heck reactions of [p-IPhSiO1.5]12. To a dry 10ꢀmL Schlenk flask under N2 was added
0.50 g (0.16 mmol, 1.9 mmolꢀI) of I12DDPS, 19 mg (0.04 mmol) of Pd[P(tꢀBu3)]2, and 18 mg
(0.020 mmol) of Pd2(dba)3. 1,4ꢀdioxane (3 mL) was then added by syringe, followed by NCy2Me
ᵒ
(3.2mmol, 0.7 mL) and Rꢀstyrene (6.8 mmol). The mixture was stirred at 70 C for 48 h. Then
reaction solution quenched by filtering through 1 cm Celite, which was washed with 5 mL THF.
The solution was then precipitated into 200 mL methanol and filtered. The solid redissolved in
10 mL THF and filtered again through Celite column to remove any remaining Pd particles, and
then precipitated into 200 mL methanol.
General Heck reactions of [o-BPhSiO1.5]8. To a dry 10ꢀmL Schlenk flask under N was addꢀ
2
ed 0.50 g (0.3 mmol, 2.4 mmolꢀBr) of [BrPhSiO1.5]8 , 22 mg (0.046 mmol) of Pd[P(tꢀBu3)]2, and
21 mg (0.023 mmol) of Pd2(dba)3. 1,4ꢀdioxane (3 mL) was then added by syringe, followed by
°
NCy2Me (3.7mmol, 0.8 mL) and Rꢀstyrene (8.70 mmol). The mixture was stirred at 70 C for 24
h and then quenched by filtering through 1 cm Celite, which was washed with 5 mL THF. The
solution was then precipitated into 200 mL methanol, filtered, and the solid reꢀdissolved in 10
5

Dalton Transactions
Page 6 of 25
View Article Online
DOI: 10.1039/C7DT00373K
mL THF. This solution was then filtered again through a 1 cm Celite column to remove any reꢀ
maining Pd particles, and reꢀprecipitated into 200 mL methanol. Analytical data are presented in
the discussion section below.
Removal of residual Pd catalyst. To a dry 50ꢀmL Schlenk flask under N2 was added 1.0 g of
RStyrxPh8Si8O12 dissolved in 10 mL of toluene and 0.1 g of NꢀacetylꢀLꢀcysteine dissolved in 1
mL of THF. The solution was stirred overnight at room temperature and then filtered through a
short silica gel column to remove the insoluble Pdꢀcysteine complex. The filtrate was then conꢀ
centrated by rotary evaporation and precipitated into 200 mL of methanol or hexane. The product
was filtered and dried in vacuum oven overnight.
[m-AcetylPhSiO1.5]8. To a 250 mL Schlenk flask under N2, acetyl chloride (19.50 mL, 278.4
mmol) was added into AlCl3 (20.10 g, 151.2 mmol) in 80 mL of 1:1 (v/v %) ratio of CH2Cl2/CS2
solution. The mixture was stirred at 0° C under N2 for 15 min. [PhSiO1.5]8 (10 g, 9.72 mmol, ꢀPh
80 mmol) was then added to the mixture and the solution was stirred for 5 h at 0° C and then 19
h at room temperature. The reaction was quenched and the organic layer was extracted with 40
mL CH2Cl2.
The organic layer was washed with water and then was dried over sodium sulfate, the solvent
removed by rotovap and 100 mL CH2Cl2 added to the flask. The resulting suspension was filꢀ
tered. The undissolved powder was dissolved in 100 mL CH2Cl2 and passed through the column.
Then concentrated by rotovap and precipitated dropwise into 250 mL of hexane, which resulted
in a white powder. The powder was collected by filtration, washed with hexane to yield 8 g of
the product.
Sulfonylation of [PhSiO1.5]8. This was a Fridel–Crafts reaction. [PhSiO1.5]8 (10.34 g, equivaꢀ
lent to 80 mmol of phenyl groups) was suspended in dichloromethane (150 mL) and benzene
6

Page 7 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
sulfonyl chloride (28.32 g, 160 mmol) in a 250ꢀmL, threeꢀnecked, roundꢀbottomed flask
equipped with a magnetic stirrer and a condenser. AlCl3 (21.33 g, 160 mmol) was added in three
parts over a 10ꢀmin period. The mixture was stirred initially at 0˚C for a certain time and then
allowed to warm to a temperature higher than room temperature for over 2 days. The final soluꢀ
tion was poured into ice–water (150 g), and then, a pale yellow precipitate was collected by filꢀ
tration and washed with nꢀhexane (500 mL), ethanol (1500 mL), and water (1500 mL) in turn.
The resulting solid was then recovered by filtration, redissolved in 50 mL of dichloromethane,
filtered through a 1ꢀcm Celite column, reprecipitated into 700 mL of cold ethanol, and vacuumꢀ
dried for 8 h. This gave 19.05 g (8.8 mmol, 89% yield) of pale yellow powder.42
Peroxide Oxidation of Silica Core. A 4.8 g sample of [BrPhSiO1.5]8/10/12, 2.5 g of KF, and 2.0
g of NaHCO3 were added to a 250 mL roundꢀbottom flask. Then 25 mL of THF was added and
the mixture stirred until the silsesquioxane dissolved. Then, 25 mL of methanol and 20 mL of
30% H2O2 were added, whereupon the silsesquioxane precipitated. This mixture was then reꢀ
fluxed for 4 h over which time the solution became clear yellow and later precipitated white siliꢀ
ca. The solution was then decanted to remove the silica and extracted with ethyl acetate/water
three times in order to remove salts. The water layers were combined and extracted with addition
ethyl acetate to ensure complete capture of any organic compounds. The combined organic layꢀ
ers were dried over sodium sulfate and evaporated to remove the solvents. The recovered prodꢀ
ucts was analyzed by GCꢀMS, 1H NMR, or 13C NMR as discussed above or in SI. The yields for
the individual compounds are as follows.
7

Dalton Transactions
Page 8 of 25
View Article Online
DOI: 10.1039/C7DT00373K
Results and discussion
We recently extended our observation of highly selective ortho bromination of [PhSiO1.5]8 to
the larger [PhSiO1.5]10 and [PhSiO1.5]12 cages56 to ascertain selectivity differences vs cage size,
geometry and electronic ground states as it offers an extreme contrast to ICl promoted iodination
which, as noted above, occurs almost exclusively para for all cages. In contrast, nitration and
Friedel Crafts acylation and sulfonation are highly meta selective.40ꢀ42 In these previous studies,
we found that ortho bromination selectivity remains high; albeit, less selective than for
[PhSiO1.5]8 primarily because the phenyl groups sit on the cages at average angles of 72° and 60°
partially blocking access to the cage face where interaction with the cage LUMO guides the
bromination process.36,37
As discussed in the introduction, the ability to selective ortho or para halogenate 8 to 12
phenyl groups at once coupled with the ability to further functionalize these cage bound phenyls
via catalytic crossꢀcoupling reactions provides routes to quite differently structured organic moiꢀ
eties. The opportunity to effect hydroxylation by Fꢀ/H2O2 promoted cleavage of the SiꢀC bonds28ꢀ
35 offers unique utility if it can be developed as a general route to functionalized phenols, potenꢀ
tial precursors to pharmaceuticals and/or agrochemicals. This then provides the motivation for
the current work.
In the following sections we first briefly discuss efforts to assess ortho bromination selectivity
in the larger cages which we recently learned to synthesize in high yields as opposed to the tradiꢀ
tional [PhSiO1.5]8.36,37 Thereafter, we present studies on Fꢀ/H2O2 promoted cleavage of [o-
BrPhSiO1.5]8, followed by initial cleavage studies on stilbenes produced via Heck cross coupling
reactions with pꢀRꢀstyrene where R = Me and CN per Figure 1. Similar studies are presented
thereafter for para and meta derivatives of the PhSQs.
8

Page 9 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
Figure 1. 4,2’-R,OHꢀstilbene and 4,4’-R,OHꢀstilbene products using a [PhSiO1.5]10 Nanoꢀ
reactor.
Synthesis studies. We recently determined that bromination of [PhSiO1.5]8,10,12 without cataꢀ
lyst, at mild temperatures (30ꢀ60 °C, see experimental section) provides 60ꢀ85 % ortho selectiviꢀ
ty following recrystallization depending on the cage size as summarized in Table 1.36 This selecꢀ
tivity occurs despite the very bulky nature of the cage attached ortho to the bromination site and
that these cages exhibit electron withdrawing behavior similar to ꢀCF3, Table 2.57
Table 1 compares selectivity for both oꢀbromination and pꢀiodination using Fꢀ/H2O2 cataꢀ
lyzed generation of the corresponding phenols. Because we have previously reported the sucꢀ
cessful functionalization of both types of halogenated cages using multiple catalytic cross couꢀ
pling reactions,34,35 an obvious opportunity arose to produce the corresponding phenols.
Table 1. Bromination of [PhSiO1.5]x (x = 8, 10 or 12) and Fꢀ/H2O2 SiꢀC cleavage† products.
characterization
Max in
MALDI
Temp.
° C
Area %†
Ortho
†% 2ꢀ
SQ
bromophenol47
[PhSiO1.5]8
[PhSiO1.5]10
[PhSiO1.5]10
[PhSiO1.5]12
[PhSiO1.5]12
BrPh8Si8O12
Br4Ph10Si10O15
Br9Ph10Si10O15
Br6Ph12Si12O18
Br6Ph12Si12O18
Br9Ph12Si12O18
30ꢀ40
30ꢀ40
30ꢀ40
40
40
50ꢀ55
85
78
75
60
60
62
≈ 90
75
75
60
60
[PhSiO1.5]12
60
[Br2PhSiO1.5]8
90 % 2,5 dibromo
phenol
PhSiCl3
BrPhSiCl3
5††
90 %
4ꢀiodophenol
[IPhSiO1.5]8
[IPhSiO1.5]10
[IPhSiO1.5]12
†From GC analysis of Fꢀ/H2O2 cleavage of Phenyl SiꢀC bond.58 ††70 % meta, 25 % para.59
The goal here has been to demonstrate the breadth of this type of hydroxylation rather than to
undertake detailed efforts to optimize it. Again, as noted above, one molar equivalent of cage can
9

Dalton Transactions
Page 10 of 25
View Article Online
DOI: 10.1039/C7DT00373K
Table 2. Ipso 13C for [PhSiO1.5]8,10,12 and [BrPhSiO1.5]8,10,12 and selected model compounds.
Cage
Ipso carbon
13C (ppm)
130.92
Cage
Ipso carbon
13C (ppm)
129.06
[PhSiO1.5]8
[PhSiO1.5]10
[PhSiO1.5]12
NO2C6H5
[BrPhSiO1.5]8
[BrPhSiO1.5]10
[BrPhSiO1.5]12
oꢀBrNO2C6H4
oꢀCF3BrC6H4
PhSiCl3
130.55
129.01
130.83
128.99
148.30
152.80
CF3C6H5
130.90
130.260
131.55
PhSi(OEt)3
[Ph2SiO]4
131.77
134.42
produce 8ꢀ12 molar equivalents of phenolic products as suggested by Scheme 1 and Tables 3, 6
and 7 below. This aspect suggests that these cages can be termed nanoreactors. This approach
appears to offer access to phenolic derivatives not easily generated by any other means as noted
in the literature.34,35,45ꢀ50
Ortho-functionalized phenols
The first step in these studies was to verify the Table 1 data in more detail. GCꢀMS analysis
for Fꢀ/H2O2 cleavage of [BrPhSiO1.5]8 and selected cross–coupling products provides the data
presented in Table 3. Three peaks are observed in the GC at retention times (R) = 4.3, 5.4, and
7.1 min, see Table S1 also. The first peak is phenol arising from unsubstituted phenyls and acꢀ
counts for 30 % of the material in an unꢀrecrystallized sample.
The peaks at R = 5.4 and 7.1 min offer identical mass spectra per Figures S1 and S2. The MS
library suggests that they are 3ꢀ and 4ꢀbromophenols; however, the published crystal structure of
a recrystallized sample shows the compound to be 85 % ortho substituted.36,37 This is in keeping
with the Table 3 GC analyses, which shows one isomer (R = 5.4) integrates to ≈ 92 % of the total
area. Having established the identity of the various isomers arising from Fꢀ/H2O2 cleavage of the
starting brominated compounds, the next step was to demonstrate the potential of this approach
to generate more sophisticated compounds.
Our objective here was to use a set of well characterized compounds that also offered potenꢀ
tial problems with respect to H2O2 oxidation. Thus, we previously reported the syntheses of mulꢀ
tiple different stilbene derivatives from [o-BrPhSiO1.5]8 without making any attempt to produce
phenol derivatives.43,44 In principle, stilbene derivatives may be more difficult to effect Fꢀ/H2O2
cleavage than other compounds given the exposed double bond. To this end, we chose the rather
innocuous p-methyl and pꢀcyano derivatives as initial test cases.
10

Page 11 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
Table 3. GC of peroxide cleavage of oꢀfunctionalized SQs.
Sample
R time Area
Formula
MW
m/e (Intensity %)
Assigned Species
Phenol
Yield
%
(min)
4.3
5.4
%
[oꢀBrPhSiO1.5]8
30
53
17
92
8
C6H6O
94
94(100), 66(40), 40(15)
C6H5BrO
C6H5BrO
C6H5BrO
C6H5BrO
C6H5BrO
C6H5BrO
C6H5BrO
C6H5BrO
C15H14O
C15H14O
C6H6O
173
173
173
173
173
173
173
173
210
210
94
173(65), 93(30), 65(100) Phenol, 2ꢀbromo
173(80), 93(60), 65(100) Phenol, 4ꢀbromo
173(70), 93(30), 65(100) Phenol, 2ꢀbromo
173(65), 93(60), 65(100) Phenol, 4ꢀbromo
173(90), 93(35), 65(100) Phenol, 2ꢀbromo
173(75), 93(65), 65(100) Phenol, 4ꢀbromo
173(85), 93(35), 65(100) Phenol, 2ꢀbromo
173(80), 93(60), 65(100) Phenol, 4ꢀbromo
7.1
[oꢀBrPhSiO1.5]8
Recrystallized
[oꢀBrPhSiO1.5]10
5.4
7.1
45±3
5.4
7.1
73
27
62
38
72
28
34
66
[oꢀBrPhSiO1.5]12
5.4
7.1
[o-MeStyrPh
SiO1.5]8
10.8
11.3
4.2
210(100), 195(50),
179(30), 210(85)
94(100), 66(55), 40(25)
221(100)
4,2’- Me,OHꢀstilbene
4,4’- Me,OHꢀstilbene
Phenol
47±2
[oꢀCNStyrPh
36±3
SiO1.5]7 [PhSiO1.5] 11.9
C15H11NO
221
4,2’- CN,OHꢀstilbene
Mass spectral analysis for Fꢀ/H2O2 cleavage of [o-MeStyr7Ph8Si8O12]. The equivalent analꢀ
yses of the derivatives of the ortho brominated cages are as follows. The GC (from GCꢀMS data)
of peroxide cleavage products of [o-MeStyr7Ph8Si8O12] also show two peaks (see Table 3) with
R = 10.8 and 11.3 min. The peak at R = 10.8 can be identified from the MS library to be 4,2’-
Me,OHꢀstilbene whereas the peak at 11.3 min is 4,4’-Me,OHꢀstilbene.
Figures S5 and S6 provide the mass spectral analyses associated with Table 3 data. The paraꢀ
derivative is roughly 30 % of the integrated area and the ortho derivative then is approximately
70%. Unfortunately, the separation in the GC is not as clean as observed in Table S1 as might be
expected for more polar compounds; consequently, these areas provide only a qualitative measꢀ
ure of the composition. The reader is reminded that these studies were not optimized. Further,
note that the selectivities to hydroxylated species are > 65 % out of a 100 % conversion. These
results would appear to be superior to the two examples noted above where selectivities were
high but conversions quite low.
Mass spectral analysis for Fꢀ/H2O2 cleavage of [oꢀcyanoStyr7Ph8Si8O12]. The analyses for
this compound and the resulting peroxide cleaved products are as follow. Figure S7 shows the
MALDI of as synthesized [oꢀcyanoStyr7Ph8Si8O12]. The [oꢀcyanoStyrPhSiO1.5]8 parent ion + Ag
is m/z = 2158.
The GC of the peroxide cleavage products shows three peaks at R = 4.2, 7.9 and 12 min. The
peak at R = 4.2 is phenol from unsubstituted phenyl and R = 7.9 is ubiquitous in these studies
11

Dalton Transactions
Page 12 of 25
View Article Online
DOI: 10.1039/C7DT00373K
and arises from butylated hydroxytoluene plasticizer extracted from the rubber septum used to
seal the cleavage reaction vials. The remaining broad peak at R = 12 min is the target product,
see Figure S8 and Table 3. The cleavage gave 66% pure 4,2’-CN,OHꢀstilbene, while the remainꢀ
der is phenol from unfunctionalized phenyls.
Table 4. Fꢀ/H2O2 Cleavage yields oꢀphenol compounds for minimum of 3 attempts.
Type
Name
Starting
cmpd
mmol
4.4
Product
Name
Product Yield
mmol
%
Ortho
[oꢀBr7Ph8Si8O12]
2ꢀBromophenol
2.0
45±3
[oꢀMestyr7 Ph8Si8O12]
[oꢀBr7Ph8Si8O12]
3.8
3.6
4,2’-Me,OHꢀstilbene
4,2’-CN,OHꢀstilbene
1.8
1.3
47±2
36±3
[oꢀCyanoStyr7Ph8Si8O12]
[oꢀBr7Ph8Si8O12]
Para-functionalized phenols
Mass spectral analysis for Fꢀ/H2O2 cleavage of [p-IPhSiO1.5]12. Using the cleavage conditions
described in the experimental section, we assessed the various products via GCꢀMS, NMR, FTꢀ
IR. Figure S9 shows the MALDIꢀToF of the parent [p-IPhSiO1.5]12, the data are selfꢀexplanatory.
It should be noted that [IPhSiO1.5]12 reflects an average of the number of iodinated species preꢀ
sent per molecule while MALDIꢀToF spectra shows still other species. (e.g. I11Ph12Si12O18,
I13Ph12Si12O18, etc).
Likewise, the peroxide cleavage products for [p-IPhSiO1.5]8,10,12 are all essentially identical
per Table 1. We present here data for the [PhSiO1.5]12 analog as this nanoreactor provides the
most hydroxylated molecules per cage. We see two relevant peaks at R = 6.4 and 7.8 min with
corresponding integration of 5 and 95 %, Table 5. The mass spectra for both peaks (Figures S10
and S10) are identical and the automated search of the mass spec library identifies these products
both as 3ꢀiodophenol.
12

Page 13 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
Table 5 summarizes the mass spec data for all compounds and provides an interpretation of
the most intense ions. Introduction of standard 2, 3 and 4ꢀiodophenol samples to the GCꢀMS
shows that the peak at R = 6.4 min is 2ꢀiodophenol and that at 7.8 is the 4ꢀiodophenol as conꢀ
1
firmed by H NMR of the isolated cleavage product, Figure S12, as compared with that of an
authentic sample in Figure S13. Figure S14 shows the FTIR of the isolated sample and Figure
S15 shows the FTIR of the authentic sample.
Mass spectral analysis of p-methylstilbene from [p-MeStyrPhSiO1.5]12. As noted just above,
the key to the utility of our suggested approach is not just to produce ortho and para substituted
halogenated phenols but to generate more sophisticated derivatives as models of potential efforts
to generate ortho and para phenols in discovery efforts. We recognize that some substituents
may not survive peroxide cleavage but given that we have not attempted to optimize the process
in any way, the results presented here offer reasonable hope for this new approach.
In general, the yields of the phenolic derivatives: 4,4’-Me,OHꢀstilbene, 4,2’-Me,OHꢀstilbene,
4,4’-CN,OHꢀstilbene and 4,2’-CN,OHꢀstilbene range from 50 % for the Me compounds to 35ꢀ40
% for the CN compounds. This means that the unoptimized yields range from 3ꢀ6 molar equivaꢀ
lents of phenol per cage. In principle, the pꢀcyano compounds are most likely to be susceptible to
peroxide oxidation given that the electron withdrawing CN groups should aid oxidation of the
stilbene on the cage or cleaved phenol product.
The GC trace of peroxide cleaved [p-MeStyrPhSiO1.5]12 (Figures S16 and S17) shows three
peaks with residence times recorded in Table 5. The peak at R = 7.9 min is the plasticizer noted
above. The peak at R = 10.6 min was identified as the epoxidized 4,4’- Me,OHꢀstilbene. The
peak at R = 11.2 min is 4,4’- Me,OHꢀstilbene per the mass spec results. As we point out above,
one might expect the stilbene double bonds to undergo ready oxidation under the reaction condiꢀ
tions. This likely account for the lower yields than found for the simple halogenated starting maꢀ
terials noted above.
The determination of the R = 7.9 peak comes from the Figure S16 mass spectrum, which has
a parent ion at m/z = 228, 18 mass units higher than that for the 4,4’- Me,OHꢀstilbene mass specꢀ
trum shown in Figure S17. We presume that this means the initially formed epoxide ring opens
thus the added mass is for one water. This peak is just ≈ 1 % of the integrated area for the peaks
shown. In contrast, the integration for the peak at R = 10.6 min is ≈ 96 % of the total area (see
Table 5) and offers the mass spectral analysis seen in Table S1.
13

Dalton Transactions
Page 14 of 25
View Article Online
DOI: 10.1039/C7DT00373K
Based on our identification of the peroxide cleaved product of [IPhSiO1.5]12 as being the pꢀ
iodophenol, the only product that should form from peroxide cleavage of [p-MeStyrPhSiO1.5]12
would be 4,4’- Me,OHꢀstilbene. As can be seen, it is by far the major product. The ion intensities
of the parent and major ion fragments are presented in Table 5. Note that Tables 3 and 5 represent
efforts to demonstrate reproducibility in these studies rather than further optimization.
Table 5. GC of peroxide cleavage of Paraꢀfunctionalized SQs.
Sample
R time
(min)
6.4
Area
%
5
95
Formula
MW
m/e (Intensity%)
Assigned species
Yield
%
[pꢀIPhSiO1.5]12
C6H5IO
C6H5IO
220
220
220(100), 93(40), 65(85)
220(100), 93(75), 65(65)
Phenol, 2ꢀiodoꢀ
Phenol, 4ꢀiodoꢀ
7.8
[pꢀIPhSiO1.5]12
[pꢀIPhSiO1.5]8
6.2
7.8
4.5
6.4
7.8
2
C6H5IO
C6H5IO
C6H6O
C6H5IO
C6H5IO
220
220
94
220
220
228
210
194
194
220(100), 93(85), 65(35)
220(100), 93(70), 65(65)
94(100), 66(35), 40(15)
220(100), 93(30), 65(55)
220(100), 93(65), 65(50)
Phenol, 2ꢀiodoꢀ
Phenol, 4ꢀiodoꢀ
Phenol
Phenol, 2ꢀiodoꢀ
Phenol, 4ꢀiodoꢀ
4,2’- Me,OHꢀstilbene
4,4’- Me,OHꢀstilbene
αꢀmethylstilbene
54±2
57±2
44±3
98
5
3
92
*
[p-MeStyrPh
SiO1.5]12
[p-MeStyrPh
SiO1.5]8
10.6
11.2
8.7
2
C15H16O2
C15H14O
C15H14
228(100), 178(90)
98
12
88
210(100), 195(30),179(20)
194(85), 179(100), 115(30)
9.7
C15H14
194(100),179(100),115(25) αꢀmethylstilbene
TBAF Cleavage
[pꢀCNStyr
PhSiO1.5]12
12.5
100
C15H11NO
221
221(100) 4,4’- CN,OHꢀstilbene
* epoxidized derivative of 4,4’- Me,OHꢀstilbene
Note that the retention time for the ortho derivative is ≈ 0.4 min shorter than for the paraꢀ
phenol as might be anticipated given that the para derivative is likely more polar and therefore has
a longer residence time in the GC. If we assume that the peroxide cleavage results for the forꢀ
mation of oꢀbromophenol are more likely to be correct then we can suggest that the same ratio
(1/99) of 4,2’-Me,OHꢀstilbene vs 4,4’-Me,OHꢀstilbene holds in the materials produced here. The
mass spectral analyses shown in Figures S16 and S17 are summarized in Table 5. For 4,2’-
Me,OHꢀstilbene, the mass peak shows MW = 228 that is 18 units (H2O) more than usual
MW(210) of 4,2’-Me,OHꢀstilbene that is due to epoxidation of the double bond followed by ring
opening as noted above.
In a separate study, we used nBu4NF to cleave the SiꢀC bonds in [p-Mestyr7Ph8Si8O12] withꢀ
out peroxide to isolate p-methylstilbene. Two products are seen in the GC (Table S1) with inteꢀ
gration ratios of 12:88 and residence times of 8.7 and 9.7 min, Table 5. The mass spec library
14

Page 15 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
identifies two types of methylstilbenes. We presume that one of these is from regioꢀselective
insertion addition of the PhꢀPd to methylstyrene as expected and produces 88% 1ꢀmethylꢀ4ꢀ(2ꢀ
phenylethenyl) while there is small amount (12%) of the 1,1ꢀaddition product as suggested in
Figure 2. The mass spectra of both compounds are provided in Figures S18 and S19.
a.
b
Figure 2. Competitive Heck coupling for methylstilbene a. 1,1ꢀphenyltolylethylene and b. 1ꢀ
methylꢀ4ꢀ(2ꢀphenylethenyl).
Mass spectral analysis for Fꢀ/H2O2 cleavage of [pꢀcyanoStyrPhSiO1.5]12 The GC of the peroxꢀ
ide cleavage products from [pꢀcyanoStyrPhSiO1.5]12 (Table S1) shows three peaks at R = 7.9,
12.5 and 12.8 min. Table 5 records the integrations and assigned species for some of these peaks
and records the mass spec. intensities for the principle ions observed.
The R = 7.9 min peak is butylated hydroxytoluene. Both peaks at 12.5 and 12.8 min provide
mass spectra (Figures S20 and S21) with similar fragmentation patterns that are not those of the
suggested cinnaminonitrile derivative of Figure S22. The width of the peak centered near 12.5
min suggests that the cyano compound is highly polar and moves very poorly in the GC in acꢀ
cord with the difference between the ortho and para phenols made from the methylstilbene comꢀ
pounds. Again the residence times of the “ortho” and “para” derivatives as well as the peak
shapes support the concept that two different compounds have been made wherein the phenolic
group positions differ as anticipated from the peroxide cleavage of the starting halogenated pheꢀ
nyl cages. The GCs of ortho and para phenol derivatives of cyanostilbene shows that the Rꢀtime
of the ortho derivative is ≈ 12 min versus para, which is ≈ 12.5 min.
Again, as noted above, the Fꢀ/H2O2 cleavage yields for generation of o-bromophenol and p-
iodophenol are typically 55ꢀ85 % which equates with 4ꢀ5 and 6ꢀ7 molar equivalents per mole of
cage starting material. The Fꢀ/H2O2 cleavage for 4,2’-Me,OHꢀstilbene and 4,4’-Me,OHꢀstilbene
averages about 50 % which equates to 4 and 6 molar equivalents per mole of cage starting mateꢀ
rial. In contrast the more easily oxidized 4,2’-CN,OHꢀstilbene and 4,4’-CN,OHꢀstilbene Fꢀ/H2O2
15

Dalton Transactions
Page 16 of 25
View Article Online
DOI: 10.1039/C7DT00373K
cleavage product yields average 40 % which equates with 3 and 5 molar equivalents of phenol
per cage (Table 6).
Table 6. Fꢀ/H2O2 Cleavage yields pꢀphenol compounds for minimum of 3 attempts.
Type
Name
Starting
cmpd
mmol
7.3
Product
Name
Product
mmol
%
Yield
[p-I7Ph8Si8O12]
4-Iodophenol
4.2
2.1
1.8
57±2
54±2
44±3
Para
[p-I12PhSiO1.5]12
3.9
3.8
4-Iodophenol
[p-Mestyr12Ph12Si12O18]
[p-I12Ph12Si12O18]
4,4’-Me,OH-stilbene
[p-Cyanostyr7Ph8Si8O12]
[p-I7Ph8Si8O12]
3.6
4,4’-CN,OH-stilbene
1.5
39±3
Meta-functionalized phenols
As noted above, our objective here is to demonstrate that SQs can act as nanoreactors to proꢀ
duce ortho, para and meta phenol derivatives in acceptable to high yields. Thus, we also syntheꢀ
sized three different meta derivatives and characterized them especially with respect to their perꢀ
oxide cleavage products, anticipating high yields of pure meta functionalized phenols.
Mass spectral analysis for Fꢀ/H2O2 cleavage of [m-AcetylPhSiO1.5]8 Thus, we were able to
synthesize [m-AcetylPhSiO1.5]8 by FriedelꢀCrafts acylation of octaphenylsilsesquioxane
[PhSiO1.5]8 with CH3COCl (Figure 3). This reaction has the highest yields in these series of
compounds, and shows just one main GC peak at R = 8.3 min due to 3ꢀhydroxyacetophenone
(Table 7). The sample is pure, fully converted and shows no traces of ortho, para or diacetylated
species. 1HꢀNMR integration of the acetyl methyl protons using the optimized formylation reacꢀ
tion conditions, has been reported previously, giving a high meta/para ratio of > 99:1.61
Mass spectral analysis for Fꢀ/H2O2 cleavage of [m-NitroPhSiO1.5]8 Analysis of peroxide
cleavage of [m-NitroPhSiO1.5]8, (Figure 4) shows three peaks at R = 6.5 and 8.7 min with ratios
16

Page 17 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
of 18, 72 due to para and meta phenols with ratios of para/meta = 25/75. There is a trace at R =
9 min (10%) of dinitro phenol (see Table 7).
Table 7. GC of peroxide cleavage of Metaꢀfunctionalized SQs.
Sample
R time Area MW
m/e (Intensity %)
Assigned species
Yield %
76±2
min
%
[m-AcetylPhSiO1.5]8
[m-NitroPhSiO1.5]8
8.3
100
136
136(65),121(100),93(65),65(45)
3ꢀHydroxy
Acetophenone
6.5
8.7
9
18
72
10
139
139
184
139(100),109(45),81(55),65(80)
139(100), 93(20), 65(80)
Phenol, 2ꢀNitro
Phenol, 3ꢀNitro
Phenol, DiNitro
54±3
65±2
182(10), 165(75), 89(100), 63(80)
[mꢀ(4ꢀtolueneꢀ
4.8
12.8
7
93
94
248
94(100), 66(35), 40(15)
248(100),139(100),91(60),65(75)
Phenol
sulfonyl) PhSiO1.5]8
3ꢀHydroxyꢀ1ꢀ(tolueneꢀ
4ꢀsulfonyl)benzene
Figure 3. mꢀHydroxyacetophenone: product of [m-AcetylPhSiO1.5]10 Nanoꢀreactor.
Figure 4. mꢀNitroPhenol: product of [m-NitroPhSiO1.5]10 Nanoꢀreactor.
Mass spectral analysis for Fꢀ/H2O2 cleavage of [mꢀ(4ꢀtoluenesulfonyl)PhSiO1.5]8. The [mꢀ
diphenylsulfonylSiO1.5]8 (ODPSS) was synthesized and characterized previously via oneꢀstep
Friedel–Crafts reaction in high yield (Figure 5).41 Using the same procedure, octadiphenylsulfꢀ
onylsilsesquioxane (ODPSS) was produced and the peroxide cleaved product 3ꢀhydroxyꢀ1ꢀ
(tolueneꢀ4ꢀsulfonyl)ꢀbenzene characterized via GCꢀMass (Table 7 and Figures S27-S29). A peak
in the GC is seen at an R time = 12.6 min and is due to 3ꢀhydroxyꢀ1ꢀ(tolueneꢀ4ꢀsulfonyl)ꢀ
17

Dalton Transactions
Page 18 of 25
View Article Online
DOI: 10.1039/C7DT00373K
benzene. This is the only sulfonylation product seen, and the substitution is exclusively meta
(Table 7). The overall yield of the cleavage is 65% and is 93% pure meta (Table 8).
Figure 5. mꢀHydroxyꢀ1ꢀ(tolueneꢀ4ꢀsulfonyl)ꢀbenzene: product of [mꢀdiphenylsulfonylSiO1.5]10.
Table 8. Fꢀ/H2O2 Cleavage yields mꢀphenol compounds for minimum of 3 attempts.
Type
Name
Starting
cmpd
mmol
3.9
Product
Name
Product
mmol
%
Yield
[m-NitroPhSiO1.5]8
3-NitroPhenol
2.1
2.9
54±3
76±2
Meta
[m-AcetylPhSiO1.5]8
3.8
7.4
3-Hydroxyacetophenone
[m-(4-toluenesulfonyl)
3-Hydroxy-1-(toluene-4-
sulfonyl)-benzene
4.8
65±2
PhSiO1.5]8
Conclusions
The phenyl silsesquioxane cage compounds [PhSiO1.5]8,10,12 are unique molecules that exhibit
very unusual patterns of electrophilic substitution. Although the SiO1.5 unit exhibits electron
withdrawing properties equivalent to CF3, the halogenation reactions of these cages provide high
ortho selectivity during bromination with Br2 and in contrast high para selectivity for iodination
with ICl. Only in Friedel Crafts acylation and sulfonation with AlCl3 as the catalyst do they exꢀ
hibit the expected high meta selectivity. Furthermore, Fꢀ/H2O2 can be used to cleave the phenylꢀ
cage SiꢀC bonds to generate an OH on the ipso carbon. This represents a rare opportunity to genꢀ
18

Page 19 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
erate aromatic molecules hydroxylated at either the ortho and para positions from functionalized
[RPhSiO1.5]8,10,12 generated from [XPhSiO1.5]8,10,12 where X = o-Br or p-I.
We further briefly explored the potential utility of the Fꢀ/H2O2 promoted hydroxylation for
[RPhSiO1.5]8,10,12 generated from [XPhSiO1.5]8,10,12 where X = o-Br or p-I. These efforts focused
on using RPh = p-methyl or p-cyanostilbene bound to the silica cage at the 4’ or 2’ positions.
Each cage offers the potential to generate 8, 10 or 12 of the same product molecule hence the
appellation “nanoreactor.”
In these first unoptimized efforts, we were able to synthesize: (1) 4,2’-Me,OHꢀstilbene and
4,4’-Me,OHꢀstilbene and (2) 4,2’-CN,OHꢀstilbene and 4,4’-CN,OHꢀstilbene (3) 3-nitrophenol,
3-hydroxyꢀ1ꢀ(tolueneꢀ4ꢀsulfonyl)ꢀbenzene and 3-hydroxyacetophenone in modest to high yields
(36ꢀ76%). The cyano derivatives, with the highest propensity for oxidation gave the lowest
yields. We believe these initial results were sufficiently successful to warrant further efforts to
optimize this approach. For example, one might consider running the Fꢀ/H2O2 promoted hydroxꢀ
ylation using phase transfer catalysis or reducing the reaction temperatures or changing the reacꢀ
tion solvent, or pH. Thus, our work provides potential entrée to a wide variety of complementary
hydroxylated aromatics as potential starting points for drug discovery efforts.
Acknowledgements. This work was supported as part of the Center for Solar and Thermal
Energy Conversion (CSTEC), an Energy Frontier Research Center funded by the U.S. Departꢀ
ment of Energy (DOE), Office of Science, Basic Energy Sciences (BES), under Award # DEꢀ
SC0000957. RML would like to thank the Technion, Haifa, Israel for a Lady Davis Fellowship
where portions of this manuscript were written. We thank Mr. Joseph Furgal for the ipso carbon
NMR data.
Supplementary information
Supplementary information and chemical compound information are available in the online verꢀ
sion of the paper. Correspondence and requests for materials should be addressed to RML.
19

Dalton Transactions
Page 20 of 25
View Article Online
DOI: 10.1039/C7DT00373K
References
1. Halaouli, S., Asther, M., Sigoillot, J. C., Hamdi, M. and Lomascolo, A. “Fungal tyrosinases:
New prospects in molecular characteristics, bioengineering and biotechnological
applications.” J. Appl. Microbiol. 2006, 100, 219 – 232.
2. Seo, S. Y., Sharma, V. K. and Sharma, N. “Mushroom tyrosinase: Recent prospects.” J.
Agric. Food Chem. 2003, 51, 2837 – 2853.
3. Gerdemann, C., Eicken, C. and Krebs, B.; “The crystal structure of catechol oxidase: New
insight into the function of Typeꢀ3 copper proteins.” Acc. Chem Res., 2002, 35, 183–191.
4. SanchezꢀFerrer, A.; RodriguezꢀLopez, J. N.; Canovas, F. G. and Carmona, F. G.;
“Tyrosinase: A comprehensive review of its mechanism.” Biochim Biophys Acta, 1995,
1247, 1–11.
5. Oksana, S.; Marian, B.; Mahendra, R. and Bo, S. H.; “Plant phenolic compounds for
food, pharmaceutical and cosmetics production.” J. Medicinal Plants Res., 2012, 6, 2526ꢀ
2539.
6. Georgiou, C. A.; Koupparis, M. A.; “Automated Flow Injection Spectrophotometric
Determination of paraꢀ and metaꢀSubstituted Phenols of Pharmaceutical Interest Based on
Their Oxidative Condensation with 1 ꢀNitrosoꢀ2ꢀnaphthol.” Analyst, 1990, 115, 309ꢀ313.
7. Bendary, E.; Francis, R.R.; Ali, H.M.G.; Sarwat, M.I.; Hady, S. E.; “Antioxidant and
structure–activity relationships (SARs) of some phenolic and anilines compounds.” Annals
Agri. Sci., 2013, 58, 173–181.
8. RiceꢀEvans, C. A.; Miller, N. J. and Paganga, G.; “Structureꢀantioxidant activity
relationships of flavonoids and phenolic acids.” Free Radical Biology & Medicine, 1996, 20,
933ꢀ956.
9. Neyens, E.; Baeyens J.; “A review of classic Fenton’s peroxidation as an advanced oxidation
technique.” J. Hazardous Mater. B98, 2003, 98, 33–50.
10. Das, T. K.; Wati, M. R.; Shad, K. F.; “Oxidative Stress Gated by Fenton and Haber Weiss
Reactions and Its Association With Alzheimer’s Disease.” Arch. Neurosci. 2015, 2, e20078,
DOI: 10.5812/archneurosci.20078.
20

Page 21 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
11. Pignatello, J. J.; Oliveros, E. and MacKay, A.; “Advanced Oxidation Processes for Organic
Contaminant Destruction Based on the Fenton Reaction and Related Chemistry.” Critical
Reviews in Environmental Science and Technology, 2006, 36, 1–84.
12. Machulek Jr., A.; Quina, F. H.; Gozzi, F.; Silva, V. O.; Friedrich, L. C. and Moraes, J. E. F.;
“Fundamental Mechanistic Studies of the PhotoꢀFenton Reaction for the Degradation of
Organic Pollutants.” Organic Pollutants Ten Years after the Stockholm Convention -
Environmental and Analytical Update, 2012, Chapter 11.
13. Poerschmann, J.; Trommler, U.; Górecki, T.; “Aromatic intermediate formation during
oxidative degradation of Bisphenol A by homogeneous subꢀstoichiometric Fenton reaction.”
Chemosphere, 2010, 79, 975–986.
14. Duesterberg, C. K.; Cooper, W. J.; Waite, T. D.; “Fentonꢀmediated oxidation in the presence
and absence of oxygen.” Environ. Sci. Technol. 2005, 39, 5052ꢀ5058.
15. Duesterberg, C. K.; Mylon, S. E.; Waite, T. D.; “pH effects on ironꢀcatalyzed oxidation using
Fenton’s reagent.” Environ. Sci. Technol. 2008, 42, 8522–8527.
16. Hosomi, A.; Iijima, S. and Sakurai H. “Carbonꢀsilicon bond cleavage of
organotrialkoxysilanes and organosilatranes with mꢀchloroperbenzoic acid and nꢀ
bromosuccinimide. new route to phenols, primary alcohols and bromides” Chemistry letters,
1981, 243ꢀ246.
17. Strukul, G.; “Catalytic oxidations with hydrogen peroxide as oxidant.” Catal. by Metal
Complexes, Volume 9, 1992.
18. Jones, C. W.; “Applications of Hydrogen Peroxide and Derivatives.” 1999.
19. Kaczorowska, K.; Kolarska, Z.; Mitka, K.and Kowalski, P.; “Oxidation of sulfides to
sulfoxides. Part 2: Oxidation by hydrogen peroxide.” Tetrahedron, 2005, 61, 8315–8327.
20. Mohajeri, S.; Aziz, H. A.; Isa, M. H.; Bashir, M. J.; Mohajeri, L. and Adlan, M. N.;
“Influence of Fenton reagent oxidation on mineralization and decolorization of municipal
landfill leachate.” J. Environmental Sci. and Health A, 2010, 45, 692–698.
21. Lucas, M. S.; Peres, J. A.; “Removal of COD from olive mill waste water by Fenton’s
reagent: Kinetic study.” J. Hazardous Mater., 2009, 168, 1253–1259.
22. Kitis, M.; Adams, C. D. and Daigger, G. T.; “The effects of Fenton's reagent pretreatment on
the biodegradability of nonionic surfactants.” Water Res. 1999, 33, 2561ꢀ2568.
21

Dalton Transactions
Page 22 of 25
View Article Online
DOI: 10.1039/C7DT00373K
23. Ventura, A.; Jacquet, G.; Bermond, A.; Camel, V.; “Electrochemical generation of the
Fenton’s reagent: application to atrazine degradation.” Water Res., 2002, 36, 3517–3522.
24. Gozzo, F.; “Radical and nonꢀradical chemistry of the Fenton like systems in the presence of
organic substrates.” J. Molecular Catalysis A: Chemical, 2001, 171, 1–22.
25. Shi, F.; Tse, M. K.; Li, Z. and Beller, M.; “Controlling iron catalyzed oxidation reactions:
from nonꢀselective radical to selective nonꢀradical reactions.” Chemistry, 2008, 14, 8793–
8797.
26. Laat, J.; Le, T. G.; “Effects of chloride ions on the iron(III)ꢀcatalyzed decomposition of
hydrogen peroxide and on the efficiency of the Fentonꢀlike oxidation process.” Applied Cat.
B: Environmental, 2006, 66, 137–146.
27. Haber, F. and Weiss, J.; “The catalytic decomposition of hydrogen peroxide by iron salts.”
Proc. Royal Soc. A, 1934, 147, 332–351.
28. Tamao, K.; Kumada, M.; Maeda, K. “Silafunctional compounds in organic synthesis 21. Hyꢀ
drogen peroxide oxidation of alkyenyl(alkoxy)silanes,” Tetrahedron Lett., 1984, 25, 321ꢀ324.
29. Tamao, K. and Ishida, N. “Silafunctional compounds in organic synthesis XXVI. Silyl
groups synthetically equivalent to the hydroxy group,” J. Organometallic Chem., 1984, 269
C37ꢀC39.
30. Jones, G. R. and Landais, Y. ”The Oxidation of the CarbonꢀSilicon Bond,” Tetrahedron,
1996, 52, 7599ꢀ7662.
31. Fleming, I.; Barbero, A.; Walter, D. “Stereochemical Control in Organic Synthesis Using
SiliconꢀContaining Compounds,” Chem Rev., 1997, 97, 2063ꢀ2192.
32. Barrett, A. G. M.; Head, J.; Smith, M. L.; Stock, N. S.; White, A. J. P.; Williams, D. J.;
“Fleming−Tamao Oxidation and Masked Hydroxyl Functionality:ꢁ Total Synthesis of (+)ꢀ
Pramanicin and Structural Elucidation of the Antifungal Natural Product (−)ꢀPramanicin,” J.
Org. Chem., 1999, 64, 6005–6018
33. Chiara, J. L.; García, Á.; Sesmilo, E.; Vacas, T.; “1ꢀSilylꢀ2,6ꢀdiketones:ꢁ Versatile Intermediꢀ
ates for the Divergent Synthesis of Fiveꢀ and SixꢀMembered Carbocycles under Radical and
Anionic Conditions,” Org. Lett., 2006, 8, 3935–3938.
34. Simmons, E. M. and Hartwig, J. F. “IridiumꢀCatalyzed Arene OrthoꢀSilylation by Formal
HydroxylꢀDirected CꢀH Activation,” J. Am. Chem. Soc. 2010, 132, 17092ꢀ17095.
22

Page 23 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
35. Rayment, E. J.; Summerhill, N.; Anderson, E. A. “Synthesis of Phenols via Fluorideꢀfree
Oxidation of Arylsilanes and Arylmethoxysilanes,” J. Org. Chem., 2012, 77, 7052–7060.
36. Bahrami, M.; Kieffer, J.; Hashemi, H.; Ma, X. and Laine, R. M. “Why do the [PhSiO1.5]8,10,12
cages selfꢀbrominate primarily in the ortho position? Modeling reveals a strong cage influꢀ
ence on the mechanism.” Phys. Chem. Chem. Phys., 2014, 16, 25760ꢀ25764.
37. Bahrami, M.; Furgal, J. C.; Hashemi, H.; Ehsani, M.; Jahani, Y.; Goodson III, T.; Kieffer, J.
and Laine, R. M. “Synthesis and Characterization of Nanoꢀbuilding Blocks [o-
RStyrPhSiO1.5]10,12 (R = Meꢀ, MeOꢀ, NBocꢀ and CN. Unexpected Photophysical Properties
Arising from Apparent Asymmetric Cage Functionalization as Supported by Modelling Studꢀ
ies,” J. Phys. Chem. C. DOI: 10.1021/acs.jpcc.5b02678
38. Roll, M. F.; Asuncion, M. Z.; Kampf, J.; and Laine, R. M.; “ParaꢀOctaiodophenylꢀ
silsesquioxane, [pꢀIC6H4SiO1.5]8, a Nearly Perfect NanoꢀBuilding Block.” ACS Nano, 2008,
2, 320–326.
39. Roll, M. F.; Kampf, J. W.; Kim, Y.; Yi, E.; Laine, R.M.; “NanoꢀBuilding Blocks via
Iodination of [PhSiO1.5]n forming [pꢀIꢀC6H4SiO1.5]n where n = 8, 10, 12 and a new route to
high surface area, thermally stable, microporous materials via thermal elimination of I2.” J.
Am. Chem. Soc. 2010, 132, 10171–10183.
40. Kim, S.G.; Choi, J.; Tamaki, R.; Laine, R. M.; “Synthesis of aminoꢀcontaining oligoꢀ
phenylsilsesquioxanes.” Polymer, 2005, 46, 4514–4524.
41. Brick, C.; “Functionalization of Phenylsilsesquioxane.” Ph.D. Dissertation, University of
Michigan, 2005.
42. Li, Z.; Yang. R.; “Synthesis, Characterization and Properties of a Polyhedral Oligomeric
Octadiphenylsulfonylsilsesquioxane,” J. Appl. Polymer Sci., 2014, 131, 40892.
43. Sulaiman, S.; Zhang, J.; Goodson, III, T.; Laine, R. M. “Synthesis, Characterization and Phoꢀ
tophysical Properties of Polyfunctional Phenylsilsesquioxanes: [oꢀRPhSiO1.5]8, [2,5ꢀ
R2PhSiO1.5]8, and [R3PhSiO1.5]8 .” J. Mater. Chem. 2011, 21, 11177ꢀ11187.
44. Laine, R. M.; Sulaiman, S.; Brick, C.; Roll, M.; Tamaki, R.; Asuncion, M. Z.; Neurock, M.;
Filhol, J. S.; Lee, C.Y.; Zhang, J.; Goodson III, T.; Ronchi M.; Pizzotti, M.; Rand, S. C.; Li,
Y. “Synthesis and photophysical properties of stilbene octasilsesquioxanes. Emission behavꢀ
ior coupled with theoretical modeling studies suggest a 3ꢀD excited state involving the silica
core.” J. Am. Chem. Soc. 2010, 132, 3708–3722.
23

Dalton Transactions
Page 24 of 25
View Article Online
DOI: 10.1039/C7DT00373K
45. Laine, R. M. and Roll, M. F. “Polyhedral Phenyl silsesquioxanes” Macromolecules, 2011, 44,
1073ꢀ1109 and references therein.
46. a. Koerts, J.; Velraeds, M. M. C.; Soffers, A. E. M. F.; Vervoort, J.; Rietjens, I. M. C. M.;
“Influence of Substituents in Fluorobenzene Derivatives on the Cytochrome P450ꢀCatalyzed
Hydroxylation at the Adjacent Ortho Aromatic Carbon Center.” Chem. Res. Toxicol. 1997,
10, 279ꢀ288. b. Sarabia, S. F.; Zhu, B. T.; Kurosa, T.; “Mechanism of Cytochrome P450ꢀ
Catalyzed Aromatic Hydroxylation of Estrogens.” Chem. Res. Toxicol. 1997, 10, 767ꢀ771.
47. a. Mitoma, C.; Posner, H. S.; Reitz. H. C. and Udenfriend, S.; “Enzymatic Hydroxylation of
Aromatic Compounds.” Arch. Biochem. And Biophys. 1956, 61, 431ꢀ441. b. Ullrich, R. and
Hofrichter, M., “Enzymatic hydroxylation of aromatic compounds.” Cell. Mol. Life Sci.
2007, 64, 271 – 293 and references therein.
48. a. Lücke, B.; Narayana, K.V.; Martin, A. and Jähnisch, K., “Oxidation and ammoxidation of
aromatics.” Adv. Synth. Catal. 2004, 346, 1407ꢀ1424. b. Mukherjee, P.; Bhaumik, A.;
Kumar, R. “Ecoꢀfriendly, Selective Hydroxylation of Cꢀ7 Aromatic Compounds Catalyzed
by TSꢀ1/H2O2 System under Solventꢀfree SolidꢀLiquidꢀLiquidꢀType Triphase Conditions.”
Ind. Eng. Chem. Res. 2007, 46, 8657ꢀ8664.
49. Tani, M.: Sakamoto, T.: Mita, S.: Sakaguchi, S. and Ishii, Y.; “Hydroxylation of benzene to
phenol under air and carbon monoxide catalyzed by molybdovanadophosphoric acid.” Angew.
Chem. Int. Ed. Engl. 2005, 44, 2586ꢀ2588.
50. Hamilton, G. A.; Hanifin Jr., J. W.; Friedman, J. P.; “The Hydroxylation of Aromatic
Compounds by Hydrogen Peroxide in the Presence of Catalytic Amounts of Ferric Ion and
Catechol. Product Studies, Mechanism and Relation to Some Enzymic Reaction.” J. Am.
Chem. Soc., 1966, 88, 5269ꢀ5272.
51. Hamilton, G. A.; Friedman, J. P.; Campbell, P. “The Hydroxylation of Anisole by Hydrogen
Peroxide in the Presence of Catalytic Amounts of Ferric Ion and Catechol. Scope,
Requirements, and Kinetic Studies.” J. Am. Chem. Soc., 1966, 88, 5266ꢀ5268.
52. Ehrich, H.; Schwieger, W; Jähnisch, K; “Investigations on the selective oxidation of
benzonitrile using nitrous oxide catalyzed by modified ZSMꢀ5 zeolites.” Applied Catalysis A:
General, 2004, 272, 311–319.
24

Page 25 of 25
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT00373K
53. Yang, J.; Sun, G.; Gao, Y.; Zhao, H.; Tang, P.; Tan, J.; Lub, A. and Ma, D.; “Direct catalytic
oxidation of benzene to phenol over metalꢀfree grapheneꢀbased catalyst.” Energy Environ.
Sci., 2013, 6, 793–798.
54. a. Ossadnik, C.; Veprek, S.; Marsmann, H.C.; Rikowski, E. “Photolumineszenzeigenshaften
von substiturierten Silsesquioxanen der Zusammensetzung Rn(SiO1.5)n,” Monat. für Chem.
1999, 130, 55ꢀ68. b. Azinovic, D.; Cai, J.; Eggs, C.; Konig, H.; Marsmann, H.C.; Veprek, S.
“Photoluminescence from silsesquioxanes R8(SiO1.5)8,” J. Luminescence, 2002, 97, 40ꢀ50.
55. Roll, M.F.; Mathur, P., Takahashi, K.; Kampf, J. W.; Laine, R. M. “[PhSiO1.5]8 promotes
selfꢀbromination to produce [oꢀBrPhSiO1.5]8: further bromination gives crystalline [2,5ꢀ
Br2PhSiO1.5]8 with a density of 2.32 g cm−3 and a calculated refractive index of 1.7 or the
tetraicosa bromo compound [Br3PhSiO1.5]8” J. Mater. Chem., 2011, 21, 11167ꢀ11176.
56. J. C. Furgal, T. Goodson III, R. M. Laine, “D5h [PhSiO1.5]10 synthesis via F− catalyzed
rearrangement of [PhSiO1.5]n. An experimental/computational analysis of likely reaction
pathways, Dalton Trans., 2016, 45, 1025.
57. Feher, F.J.; Budzichowski, T.A. "Syntheses of highlyꢀfunctionalized polyhedral
oligosilsesquioxanes." J. Organometallic Chem., 1989, 379, 33ꢀ40.
58. Brick, C.M. Tamaki, R.; Kim, S.ꢀG.; Asuncion, M.Z.; Roll, M.; Nemoto, T.; Ouchi, Y.;
Chujo Y.; Laine, R.M. “Spherical, Polyfunctional Molecules Using Poly(bromophenylsilꢀ
sesquioxane)s as Nanoconstruction Sites.” Macromolecules, 2005, 38, 4655ꢀ4660.
59. Private Communication, Dr. S. Sulaiman, Gelest Inc. Gelest Product SIB1903.0SIB1903.0
60. Newmark, R. A.; Hill, J. R. “Carbonꢀ13–fluorineꢀ19 coupling constants in benzotrifluorides,”
Org. Mag. Res. 1977, 9, 589ꢀ592.
61. Kawakami, Y.; Kabe Y.; “Novel metaꢀSelective FriedelꢀCrafts Acylation of
Phenylsilsesquioxane.” Chem. Lett. 2010, 39, 1082ꢀ1083.
25